BMPR2 mutations, Neointimal Transformation and Pulmonary Arterial Hypertension

BMPR2 突变、新内膜转化和肺动脉高压

基本信息

批准号：
10436203
负责人：
Mark Robert Nicolls
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436203
关键词：
Animals Arachidonate 5-Lipoxygenase Arteries Atlases Automobile Driving BMPR2 gene Binding Blood Vessels Blood capillaries Cardiopulmonary Cell Lineage Cell Proliferation Cell Therapy Cells Cellular biology Cessation of life Characteristics Chronic Clinical Coupled Cues DNA Sequence Alteration Dangerousness Data Disease Disease Pathway Endothelial Cells Endothelium Epigenetic Process Fluorescent in Situ Hybridization Future Gene Mutation General Population Genes Genetic Genetic Markers Genetic Transcription Germ-Line Mutation Goals Grant Growth Health Heart failure High Prevalence Histology Human Hypertension IL6ST gene Immunofluorescence Immunologic Individual Inflammation Inflammation Mediators Inflammatory Inherited Interleukin-1 Interleukin-6 Lead Lesion Life Link Lung Maintenance Mediating Modeling Molds Molecular Molecular Target Mutation NF-kappa B Nuclear Pathologic Processes Pathway interactions Patients Phenotype Population Post-Translational Protein Processing Prognosis Pulmonary Hypertension Pulmonary Inflammation Pulmonary artery structure Rattus Research Savings Signal Pathway Signal Transduction Smooth Muscle Myocytes Techniques Testing Therapeutic Transcription Coactivator Transcriptional Regulation Transforming Growth Factor beta Transposase Tunica Intima Vascular Diseases Vascular Endothelial Cell Vascular remodeling Veterans Veterans Health Administration arteriole base bioinformatics tool bone morphogenetic protein receptors cell transformation chromatin immunoprecipitation druggable target genetic risk factor genetic variant hemodynamics high risk human disease lung health lung pressure mortality risk mutant mutation carrier novel p65 phase II trial pressure programs pulmonary arterial hypertension pulmonary arterial pressure pulmonary artery endothelial cell receptor right ventricular failure single molecule single-cell RNA sequencing therapeutic target transcriptome transcriptomics vascular inflammation

Animals Arachidonate 5-Lipoxygenase Arteries Atlases Automobile Driving BMPR2 gene Binding Blood Vessels Blood capillaries Cardiopulmonary Cell Lineage Cell Proliferation Cell Therapy Cells Cellular biology Cessation of life Characteristics Chronic Clinical Coupled Cues DNA Sequence Alteration Dangerousness Data Disease Disease Pathway Endothelial Cells Endothelium Epigenetic Process Fluorescent in Situ Hybridization Future Gene Mutation General Population Genes Genetic Genetic Markers Genetic Transcription Germ-Line Mutation Goals Grant Growth Health Heart failure High Prevalence Histology Human Hypertension IL6ST gene Immunofluorescence Immunologic Individual Inflammation Inflammation Mediators Inflammatory Inherited Interleukin-1 Interleukin-6 Lead Lesion Life Link Lung Maintenance Mediating Modeling Molds Molecular Molecular Target Mutation NF-kappa B Nuclear Pathologic Processes Pathway interactions Patients Phenotype Population Post-Translational Protein Processing Prognosis Pulmonary Hypertension Pulmonary Inflammation Pulmonary artery structure Rattus Research Savings Signal Pathway Signal Transduction Smooth Muscle Myocytes Techniques Testing Therapeutic Transcription Coactivator Transcriptional Regulation Transforming Growth Factor beta Transposase Tunica Intima Vascular Diseases Vascular Endothelial Cell Vascular remodeling Veterans Veterans Health Administration arteriole base bioinformatics tool bone morphogenetic protein receptors cell transformation chromatin immunoprecipitation druggable target genetic risk factor genetic variant hemodynamics high risk human disease lung health lung pressure mortality risk mutant mutation carrier novel p65 phase II trial pressure programs pulmonary arterial hypertension pulmonary arterial pressure pulmonary artery endothelial cell receptor right ventricular failure single molecule single-cell RNA sequencing therapeutic target transcriptome transcriptomics vascular inflammation

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项目摘要

Patients served by the Veterans Health Administration who have chronic cardiopulmonary conditions are at high risk for death because of pulmonary hypertension (PH). A particularly dangerous form of PH, referred to as pulmonary arterial hypertension (PAH), is a vascular disease with high prevalence and poor survival among US veterans. PAH is characterized by gene variants, chronic inflammation and an occlusive remodeling of the vascular intima (neointima). Heterozygous germline mutations in BMPR2 (bone morphogenetic protein receptor 2) is the principle genetic risk factor for hereditary PAH. There is an unmet need to understand how environmental cues induce PAH in otherwise healthy BMPR2 mutation carriers. We recently showed in a new ‘2-hit’ rat model that Bmpr2 mutations, when coupled with pulmonary inflammation, elicit severe PAH in otherwise phenotypically-silent Bmpr2+/- mutant rats. PAH in this model features a proliferative and inflammatory neointima with characteristics shared by human disease. TGF-b blockade ameliorates advanced PAH and neointimal transformation in Bmpr2+/- animals and is a promising clinical therapy. Pilot single cell RNA-seq analyses of the disease rat lungs revealed that Bmpr2 mutations and an inflamed lung microenvironment cause a ‘transcriptional convergence’ of endothelial cells (ECs, originating from pulmonary arteries, arterioles and capillaries) to form the transformed neointima. Based on these results, we postulate that PAH occurs in Bmpr2 mutants because discrete endothelial transcriptional programs are modulated and result in an inflamed neointima. This proposal explores how genetic and environmental triggers may lead to neointimal formation and PAH at the cellular and molecular levels; proposed studies also search for druggable targets driving EC transformation following TGF-b treatment. Specific Aim 1 evaluates how Bmpr2 deficiency causes transcriptional convergence of ECs to form the PAH neointima and has three subaims which are to establish a molecular atlas of rat lungs in health and PAH using cutting-edge single molecular techniques (Aim 1a), then to elucidate the cellular origins of neointima by tracking specific endothelial lineage cells in evolving disease (Aim 1b), and finally to identify molecular programs responsible for the formation and maintenance of vascular lesions (Aim 1c). Specific Aim 2 explores how BMPR2 deficiency in human pulmonary arterial ECs provokes proliferative endothelial inflammation and focuses on the influence of BMPR2 deficiency on inflammatory 5- lipoxygenase (5-LO), NF-kB and IL-6 signaling. Here, the mechanisms by which BMPR2 insufficiency induces 5-LO epigenetic and post-translational modification, NF-kB transcriptional activities and classical- or trans-IL-6 signaling will be assessed. Specific Aim 3 tests whether TGF-b blockade reverses PAH by eliminating transcriptionally-convergent ECs (i.e., neointimal cells) in the lungs of Bmpr2 mutant rats. This aim investigates whether and how TGF-b inhibition reverses PAH by promoting the transcriptional ‘deconvergence’ of ECs and explores the reversibility and potential druggability of molecular targets. The overarching goal of this proposal is to create a better understanding about the formation of the neointimal layer in PAH, a pathological process responsible for vascular occlusion, high pulmonary artery pressures and right heart failure. These studies may also offer clear directions for future therapeutic avenues of direct benefit to our veteran patients.

由退伍军人卫生管理局服务的患者患有慢性心肺疾病的患者因肺动脉高压（pH）而导致死亡的风险。一种特别危险的pH形式，称为肺动脉高压（PAH）是一种血管疾病退伍军人。 PAH的特征是基因变异，慢性炎症和闭塞重塑血管内膜（新内膜）。 BMPR2中的杂合种系突变（骨形态发生蛋白受体） 2）是遗传性PAH的主要遗传危险因素。有未满足的需要了解如何环境提示在其他健康的BMPR2突变载体中诱导PAH。最近，我们在新的“ 2击”大鼠模型中显示了BMPR2突变与肺部注射相结合时，在其他表现型的BMPR2 +/-突变大鼠中引起严重的PAH。该模型中的PAH具有具有人类疾病具有特征的增殖和炎症新神经。 TGF-B封锁改善BMPR2 +/-动物的晚期PAH和新内膜转化，是一种有希望的临床疗法。疾病大鼠肺的飞行员单细胞RNA-seq分析表明，BMPR2突变和发炎的肺微环境引起内皮细胞的“转录收敛”（EC，起源于肺部动脉，动脉和毛细血管）形成转化的新内膜。基于这些结果，我们假设 PAH发生在BMPR2突变体中，因为离散的内皮转录程序是调制的并导致发炎的新神经。该提案探讨了遗传和环境触发者如何导致新的形成和PAH 细胞和分子水平；拟议的研究还搜索驱动EC转化的可吸毒目标 TGF-B治疗后。特定目标1评估BMPR2缺乏症如何引起转录 EC的收敛形成PAH Neininima，并具有三个用于建立分子的子象征使用尖端的单分子技术（AIM 1A），健康和PAH的大鼠肺的地图集，然后阐明新内膜的细胞起源是通过跟踪不断发展的疾病（AIM 1B）中的特定内皮谱系细胞和最后，确定负责形成和维持血管病变的分子程序（目标 1C）。特定目标2探索BMPR2人类肺动脉EC中的缺乏症如何挑衅增生的内皮炎症，专注于BMPR2缺乏对炎症的影响5- Lipoxygyase（5-LO），NF-KB和IL-6信号传导。在这里，BMPR2不足引起的机制 5-LO表观遗传和翻译后修饰，NF-KB转录活性以及经典或反式IL-6 信令将被评估。特定的目标3测试TGF-B封锁是否通过消除来逆转PAH BMPR2突变大鼠肺中的转录构成ECS（即新拟细胞）。这个目标调查TGF-B抑制是否通过促进转录“解剖”来逆转PAH ECS并探索分子靶标的可逆性和潜在的可药用性。总体目标建议是对PAH中新蛋白层的形成的形成更好地理解。导致血管阻塞，高肺动脉压力和右心衰竭的过程。这些研究还可以为我们的资深患者提供直接益处的未来治疗途径的明确指示。